1. Field of the Invention
The present invention relates to a pharmaceutical composition containing inosiplex or inosiplex components (as will be illustrated in detail hereinbelow) and zidovudine for treating patients suffering from AIDS and AIDS-related syndromes and asymptomatic HIV-seropositive patients. By "AIDS-related syndromes", ARC (AIDS-related complex), LAS (lymphadenopathy syndrome) and Kaposi's sarcoma are meant.
2. Discussion of the Background
Zidovudine (3'-azido-3'-deoxythymidine,AZT), a thymidine analog, is at present the only registered somewhat effective drug for the treatment of AIDS and AIDS-related syndromes. AZT is an inhibitor of the in vitro replication of some retroviruses, including HIV (Human Immunodeficiency Virus), AIDS etiological agent. Cellular thymidine kinase converts zidovudine into zidovudine monophosphate. This compound is finally converted into the triphosphate derivative which interferes with the RNA-dependent DNA-polymerase (viral reverse transcriptase), thus inhibiting viral replication. In fact, in vitro zidovudine triphosphate is incorporated into the DNA growing chains by viral reverse transcriptase, whereby DNA chain is terminated.
For a suitable and therapeutical significant plasma level to be warranted, the recommended AZT dose is 200 mg every 4 hours around the clock, even though this may interrupt the patient's normal sleep schedule.
This demanding dosing schedule is brought about by the short half-life (it averages about 1 hour) of the drug which is rapidly inactivated via glucuronidation in the liver.
Unfortunately, at the therapeutically effective doses AZT brings about severe side-effects including anemia which requires frequent blood transfusions, leukopoenia and bone marrow toxicity. Frequently, these side-effects have been severe enough to require dosage modification or even discontinuance of the drug administration. A lowered drug dose leads, however, to therapeutical unsuitable AZT plasma levels.
AZT toxicity has to date made it inadvisable to administer the drug to asymptomatic HIV-seropositive patients.
The toxicity problem of AZT is further worsened because clinical practice seems to confirm that, once the treatment with AZT is started, it must last for long time periods if not for the entire life-span of the patient.
With a view to prolonging AZT half-life and enhancing its antiretroviral effect, in any case aiming at lowering the daily dose while maintaining its therapeutical advantages, some associations of zidovudine with other drugs, some antiviral and some having different therapeutical ends, have been proposed already. Recently, 800 mg acyclovir and 100 mg AZT (one half of the recommended dose) every 4-6 hours have been reported to act synergistically against the virus. However, neurotoxicity (with profound drowsiness and lethargy) which recurred on rechallenge and resolved following discontinuance of acyclovir, has been reported (see Drug Information 88, page 396).
In the U.K. patent application GB 2 181 128 A published Apr. 15, 1987, there is disclosed the synergistic effect on zidovudine of the following drugs: alpha-, beta, and gamma-interferons, dilazep, dipyridamole, papaverine, mioflazine, hexobendine, lidoflazine, probenecid, acyclovir, interleukine II, suramine, foscarnet, HPA-23, levamisole, dideoxynucleosides (e.g. dideoxycytidine and dideoxyadenosine) and thymosine.
At any rate, the pharmacokinetics of AZT is not significantly affected by the concomitant administration of the above-identified drugs.
It, therefore, follows that the overall antiviral effect of the formulation is the sum of the effects of the two drugs, only one of them, however, (i.e. AZT) exhibiting a certain efficacy against HIV. Also the side-effects of the formulation are the sum of those of the two drugs, unless their doses are decreased. However, since--as indicated above--the only anti-HIV drug is AZT, it still remains to be proven whether the synergism between AZT and the associated drug against HIV compensates for the lower AZT dose in the formulation.